This invention pertains to cyclic amino derivatives having psychotropic and bio-affecting properties and to their preparation and use in treating patients suffering from or susceptible to psychosis, acute mania, mild anxiety states, or depression in combination with psychotic episodes by the administration of these cyclic amino derivatives. More specifically, the invention is concerned with the medicinal use of compounds having benzene or benzothiazole rings linked by sidechains to the nitrogen atom of 4-substituted-1,2,5,6-tetrahydropyridine and -piperidine moieties. These compounds possess unique dopaminergic and serotonergic profiles that make them useful in the treatment of psychosis and other mental illnesses caused by disorders of the dopaminergic and serotonergic systems.
The combination of a serotonin reuptake inhibitor, such as fluoxetine, with a dopaminergic antipsychotic agent, such as olanzapine, has been described as an improved treatment for psychosis, (European Patent Application 830864, published Sep. 22, 1997).
The preparation and use of tetrahydropyridinyl- and piperidinylindoles, 1, and related compounds as serotonin 5-HT1F agonists for the treatment of migraine, allergic rhinitis, and associated diseases has been described. Cf: U.S. Pat. No. 5,521,197 (May 28, 1996), WO Patent Publication No. 9811895 (Mar. 26, 1998) and WO 9806402 (Feb. 19, 1998), and European Patent Application 714894 (Jun. 5, 1996). 
In 1, Y=O, S, or a bond, and R1 is naphthyl, phenyl, substituted phenyl, halo, alkyl, alkylthio, alkoxy, benzyloxy, OH, CONH2.
A series of aryloxy propanolamines, including compound 2, was disclosed by Obase, et al., in Chem. Pharm. Bull., 30(2), 474-83, 1982, as antihypertensive agents. 
The synthesis and adrenergic xcex2-blocking activity of some non-cyclic amine derivatives; e.g., 3, has been described by Obase, et al., Chem. Pharm. Bull., 26(5), 1443-52, 1978, and by Franke, et al., Arzneim.-Forsch., 30(11), 1831-8, 1980. 
Some derivatives of 4-(1H-indol-3-yl)-1 piperidine-ethanol derivatives, 4, having antiarrhythmic activity were described by Clemence, et al., in U.S. Pat. No. 4,530,932 (Jul. 23, 1985). 
In 4, Ar is aryl or a selected group of heteroaryl moieties not including benzothiazole.
The preparation and use of indane and dihydroindole derivatives of indolylpiperidine compounds, 5, as dopamine D4 receptor, 5-HT receptor, and 5-HT transporter ligands was described in WO Patent Publication No. 9828293 (Jul. 2, 1998). 
In sum, none of these references suggest the novel compounds of the present invention.
A series of nitrogen-containing heterocycles linked by oxygen to alkanamines comprising, inter alia, compounds of formula 6, were disclosed and claimed for the treatment of conditions related to the reuptake of serotonin and by the 5-HT1a receptor (U.S. Pat. No. 5,741,789, Apr. 21, 1998, and U.S. Pat. No. 5,627,196, May 6, 1997). In formula 6, D represents a nitrogen-containing residue that completes 
fused pyrrolo, imidazolo, pyrido, pyrazino, pyridazino, or pyrimido moieties.
Z can be 
with R2 being absent when a double bond is intended or being hydrogen or a substituent, including a benzyl group. R3 is a non-hydrogen substituent that can be indole.
In its broadest aspect, the invention is concerned with the use of certain benzene or benzothiazole compounds linked by sidechains to indolyl-1,2,5,6-tetrahydropyridines and -piperidines or substituted 4-benzylpiperidines. These compounds possess a unique dopaminergic and serotonergic profile useful for treating CNS disorders such as psychosis and depression and they conform to Formula I: 
In Formula I:
Ar is selected from 
Z is II or III; 
Y is sulfur or oxygen;
R1 and R4 are independently selected from H and lower alkyl;
R2, R3, R6 and R7 are independently selected from H, halogen, and lower alkoxy;
R5 is selected from H, halogen, lower alkoxy and cyano;
m is an integer from 2-6;
n is zero or the integer 1 or 2; and
a dotted line represents an optional double bond.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoride, chloride, bromide or iodide substituents with fluoride, chloride and bromide preferred.
xe2x80x9cLowerxe2x80x9d refers to an alkyl or alkoxy group having from one to four carbon atoms.
Additionally, compounds of Formula I also encompass all pharmaceutically acceptable acid addition salts and/or solvates thereof. The present invention is also considered to include stereoisomers including geometric as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diasteromers, which arise as a consequence or structural asymmetry in certain compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
Several classes of Formula I compounds are intended and result from selection among benzene, benzothiazole, and II and III structural moieties. The benzothiazole classes of compounds are novel.
Preferred compounds are those wherein m is 3, n is 1 and Y is oxygen.
Preferred compound examples where Z is Formula II are shown below.
A. Benzothiazole Derivatives
5-{3-[4-(5-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{3-[4-(5-cyanoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{3-[4-(5-fluoroindol-3-yl)piperidinyl]propoxy}-2-methylbenzothiazole;
5-{3-[4-(5-cyanoindol-3-yl)piperidinyl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(5-cyanoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{4-[4-(5-cyanoindol-3-yl)piperidinyl]butoxy}-2-methylbenzothiazole;
5-{3-[4-(5-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{3-[4-(4-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(4-fluoroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(4-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{4-[4-(5-fluoroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(5-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(7-fluoroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{4-[4-(5-chloroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(5-chloroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(6-chloroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(6-chloroindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(6-chloroindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(6-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(6-bromoindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(6-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(7-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(7-bromoindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole;
5-{5-[4-(7-bromoindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole;
5-{3-[4-(5-methoxyindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]propoxy}-2-methylbenzothiazole;
5-{4-[4-(5-methoxyindol-3-yl)1,2,5,6-tetrahydropyrid-1-yl]butoxy}-2-methylbenzothiazole; and
5-{5-[4-(5-methoxyindol-3-yl)-1,2,5,6-tetrahydropyrid-1-yl]pentoxy}-2-methylbenzothiazole.
B. Benzene Derivatives
3-[1-(3-phenoxypropyl)-4-piperidinyl]-5-cyanoindole;
3-{1-[3-(2-fluorophenoxy)propyl]-4-piperidinyl}-5-cyanoindole;
3-{1-[3-(4-fluorophenoxy)propyl]-4-piperidinyl}-5-cyanoindole;
3-{1-[3-(2-methoxyphenoxy)propyl]-4-piperidinyl}-5-cyanoindole;
3-{1-[3-(3-methoxyphenoxy)propyl]-4-piperidinyl}-5-cyanoindole;
3-{1-[3-(4-methoxyphenoxy)propyl]-4-piperidinyl}-5-cyanoindole; and
3-{1-[3-(3,4-dimethoxyphenoxy)propyl]-4-piperidinyl}-5-cyanoindole.
Preferred compound examples where Z is Formula III are shown below.
5-{3-[4-(2H-benzo[d]1,3-dioxolan-4-ylmethyl)piperidinyl]propoxy}-2-methylbenzothiazole;
5-(3-{4-[(2-bromo-5-methoxyphenyl)methyl]piperidinyl}propoxy)-2-methylbenzothiazole;
5-(3-{4-[(2-bromophenyl)methyl]piperidinyl}propoxy)-2-methylbenzothiazole;
5-(3-{4-[(2-bromo-5-fluorophenyl)methyl]piperidinyl}propoxy)-2-methylbenzothiazole;
5-(3-{4-[(2,-5-difluorophenyl)methyl]piperidinyl}propoxy)-2-methylbenzothiazole;
5-(3-{4-[(3-methoxyphenyl)methyl]piperidinyl}propoxy)-2-methylbenzothiazole;
5-(3-{4-[(2-chlorophenyl)methyl]piperidinyl}propoxy)-2-methylbenzothiazole; and
5-(3-{4-[(2,5-dichlorophenyl)methyl]piperidinyl}propoxy)-2-methylbenzothiazole.
The pharmaceutically acceptable acid addition salts of the invention are those in which the counter ion does not contribute significantly to the toxicity or pharmacological activity of the salt and, as such, they are the pharmacological equivalents of the bases of Formula I. They are generally preferred for medical usage. In some instances, they have physical properties which makes them more desirable for pharmaceutical formulation such as solubility, lack of hygroscopicity, compressibility with respect to tablet formation and compatibility with other ingredients with which the substance may be used for pharmaceutical purposes. The salts are routinely made by admixture of a Formula I base with the selected acid, preferably by contact in solution employing an excess of commonly used inert solvents such as water, ether, benzene, methanol, ethanol, ethyl acetate and acetonitrile. They may also be made by metathesis or treatment with an ion exchange resin under conditions in which the anion of one salt of the substance of the Formula I is replaced by another anion under conditions which allow for separation of the desired species such as by precipitation from solution or extraction into a solvent, or elution from or retention on an ion exchange resin. Pharmaceutically acceptable acids for the purposes of salt formation of the substances of Formula I include sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, citric, acetic, benzoic, cinnamic, fumaric, mandelic, phosphoric, nitric, mucic, isethionic, palmitic, heptanoic, and others.
Compounds of Formula I, where Z=II, are most conveniently synthesized by reacting (Reaction 1) intermediate IV (shown as a benzothiazole derivative), where X is a leaving group such as halogen, aryl- or alkyl-sulfonate, or the like, with amine V in a suitable solvent, such as acetonitrile, acetone, DMSO, DMF, and the like, with suitable bases, such as trialkyl amines or sodium, potassium, or cesium carbonate, or the like, under standard alkylation conditions using catalysts such as potassium iodide. In a similar manner in Reaction 2, intermediate IV can be reacted with amine VI to give compounds of Formula I where Z is III. Other methods known to those skilled in the art may also be used. 
Intermediates of Formulas IV and VII are conveniently made by alkylating (Reactions 4, 5) appropriate benzothiazoles or benzenes with dihaloalkanes in solvents such as acetone, acetonitrile, DMSO, DMF, or the like, and in the presence of suitable bases, such as trialkyl amines or sodium, potassium, or cesium carbonate, or the like, under standard alkylation conditions. 
The piperidine intermediates of Formula V (n=1) can be prepared (Reaction 6) by condensing an N-protected-4-piperidone with a substituted indole using catalysts such as pyrrolidine, acetic acid, or the like, in solvents such as ethanol, benzene, THF, or the like, to give the the tetrahydropyridine intermediates (VIII) wherein xe2x80x9cPGxe2x80x9d represents a nitrogen protecting group. Cleavage of the N-protecting group provides the tetrahydropyridines of Formula Va. Alternatively, the tetrahydropyridine intermediates (VIII) can be reduced using using hydrogen and a suitable catalyst such as platinum, palladium, or ruthenium catalysts, in solvents such as ethanol, ethyl acetate, or the like, to give the piperidine intermediates (IX). The N-protecting group can then be cleaved using methods known to those skilled in the art to give the piperidine intermediates of Formula Vb. 
The piperidine intermediates of Formula VI are conveniently prepared by condensation of an N-protected-4-piperidone with reagents such as benzyl phosphonate esters using bases such as NaH, LDA, sodium or potassium alkoxides, or the like, in solvents such as THF, diethyl ether, or the like, to provide the benzylidene intermediate, XI. Subsequent reduction of the benzylidene group using hydrogen and platinum, palladium, or ruthenium catalysts, in solvents such as ethanol, ethyl acetate, or the like, provides the piperidine intermediate, X. The N-protecting group is then cleaved using methods known to those skilled in the art to give the piperidine intermediates of Formula II as depicted in Reaction 7. 
The reactions depicted above and their application are familiar to the practitioner skilled in organic synthesis and modifications of conditions and reagents would be readily understood. The skilled synthetic chemist would know how to adapt these processes for preparation of specific formula I compound including other compounds embraced by this invention but not specifically disclosed. Variations of the methods to produce the same compounds in somewhat different fashion will also be evident to one skilled in the art. To provide greater detail in description, representative synthetic examples are provided infra in the xe2x80x9cSpecific Embodimentsxe2x80x9d section.
The compounds of Formula I bind potently to the human 5-HT transporter and inhibit the re-uptake of endogenous serotonin. Selective serotonin reuptake inhibitors (SSRIs) are effective for the treatment of mental depression and have been reported to be useful for treating chronic pain (see: R. W. Fuller, Pharmacologic Modification of Serotonergic Function: Drugs for the Study and Treatment of Psychiatric and Other Disorders,xe2x80x9d J. Clin. Psychiatry, 47:4 (Suppl.) April 1986, pp. 4-8). Compounds of the present invention are also envisioned to be useful for treating psychosis, acute mania, mild anxiety states or depression with secondary psychotic episodes. The present compounds are also envisioned to be useful in treating obsessive-compulsive disorders, feeding disorders, anxiety disorders and panic disorders.
Like many clinically effective antipsychotic agents, the compounds of Formula I also are antagonists at the human D2L receptor as determined by [3H]-spiperone binding studies using human D2L receptors stably expressed in HEK-293 cells. Clinical studies have demonstrated that selective serotonin reuptake inhibitors (SSRIs) augment the efficacy of traditional neuroleptic antipsychotic agents in improving negative symptoms in schizophrenic patients (Silver, et al., 1998, J. Clin. Psychopharmacol. 18:208; Goff, et al., 1994, Psychopharmacology 117:417). Therefore, the compounds of Formula I possess a unique serotonergic and dopaminergic profile, making the compounds of the present invention useful for treating psychosis, and in particular, the negative symptoms in schizophrenic patients.
Another aspect of the instant invention provides a method for treating a mammal afflicted with psychosis, depression, or chronic pain which comprises administering systemically to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof.
The administration and dosage regimen of compounds of Formula I are considered to be done in the same manner as for the reference compound fluoxetine, cf: Schatzberg, et al., J. Clin. Psychopharmacology 7/6 Suppl. (1987) pp. 4451-4495, and references therein. Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgement and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness, generally the daily dose will be from about 0.05 to about 10 mg/kg, preferably 0.1 to 2 mg/kg, when administered parenterally and from about 1 to about 50 mg/kg, preferably about 5 to 20 mg/kg, when administered orally. In some instances, a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required. Systemic administration refers to oral, rectal and parenteral (i.e. intramuscular, intravenous and subcutaneous). Generally, it will be found that when a compound of the present invention is administered orally, a larger quantity of the active agent is required to produce the same effect as a similar quantity given parenterally. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level that will produce effective antidepressant effects without causing any harmful or untoward side effects.
The compounds of the present invention may be administered for antipsychotic and antidepressant purposes either as individual therapeutic agents or as mixtures with other therapeutic agents. Therapeutically, they are generally given as pharmaceutical compositions comprised of an antidepressant amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical compositions which provide from about 1 to 500 mg of the active ingredient per unit dose are preferred and are conventionally prepared as tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions.
The nature of the pharmaceutical composition employed will, of course, depend on the desired route of administration. For example, oral compositions may be in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. starch) and wetting agents (e.g. sodium lauryl sulfate). Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are employed for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection.
The compounds which constitute this invention, their methods of preparation and their biologic actions will appear more fully from consideration of the following examples, which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope. In the following examples, used to illustrate the foregoing synthetic processes, temperatures are expressed in degrees Celsius and melting points are uncorrected. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (xcex4) expressed as parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the 1H NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m), heptet (hept), quartet (q), triplet (t) or doublet (d). Abbreviations employed are DMSO-d6 (deuterodimethylsulfoxide), CDCl3 (deuterochloroform) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cmxe2x88x921).
Analytical thin-layer chromatography (TLC) was performed on 0.25 mm EM silica gel 60 F-254 coated glass plates and preparative flash chromatography was performed on EM silica gel (36-62 xcexcm). The solvent systems used are reported where appropriate. All reaction, extraction and chromatography solvents were reagent grade and used without further purification except tetrahydrofuran (THF) which was distilled from sodium/benzophenone ketyl. All non-aqueous reactions were carried out in flame-dried glassware under a nitrogen atmosphere.